Phenyl-phenethyl ketones



Patented Feb. 9, 1954 PHENYL-PHENETHYL KETONES Moses Wolf Goldberg,Upper Montclair, and Albert Israel Rachlin, Hackensack, N. J., assignorsto Hofimann-La Roche Inc., Nutley, N. J., a corporation of New Jersey NoDrawing. Application April 24, 1952,

, Serial No. 284,211

6 Claims.

Our invention relates to p- (/3-diethy1aminoethoxy phenyl-phenethylketone (Formula I) ,and the acid addition salts thereof, useful as fungicide agents.

Q-omorno o-Q-o CH2GH2N\ CzHa Formula I saturated compounds. Thus,p-(B-diethylaminoethoxy phenyl styryl ketone oxalate (Formula II) may behydrogenated to p-(fl-diethylaminoethoxy)phenyl-phenethyl ketone oxalate(Formula III).

Formula II c -omomoo-oomomn (300E COOH Formula III Other acid additionsalts may similarly be prepared by reducing the correspondingunsaturated ketone salts. Moreover, the free base form (Formula I) maybe prepared by hydrogenation of the corresponding unsaturated ketone orby neutralization of one of the acid addition salts, as, for example, byneutralization of the oxalate (Formula III) by means of sodiumhydroxide. The free base may be converted to a desired acid additionsalt by treatment with a suitable acid. For example, the saturatedketone (Formula I) may be reacted with citric acid to obtain thecorresponding citrate.

The experimental material which follows illustrates the production ofour novel compounds, both in the form of the free base and in the formof several typical acid addition salts. Since p-(fl-diethylaminoethoxy)phenyl styryl ketone is, itself, new, both as afree base and in the form of acid addition salts, the experimentalportion of this application also presents data disclosing the productionof the styryl compounds.

EXPERIMENTAL p-Hydroxyphenyl styryl ketone To a stirred solution ofgrams of sodium hydroxide in 1 liter of water (30 C.) was added 136grams of p-hydroxyacetophenone and 500 cc. of ethanol. Benzaldehyde cc.,grams) was added and the solution was stirred at room temperature for 24hours. The solution was poured into 3 liters of water and, withstirring, the mixture was acidified to Congo red with concentratedhydrochloric acid. The product was filtered, washed with 2 liters ofwater and then it was air dried. Recrystallized from 1,300 cc. ofethanol, the product (p-hydroxyphenyl styryl ketone) melted at I'll-172C.

p-(p-Diethylaminoethoxy)phenyl styryl Icetone oxalate Sodium methoxide(37 grams) was added to a solution of 147 grams of p-hydroxyphenylstyrylketone in 2 liters of chlorobenzene contained in a 5 liter stirred flaskequipped with a downward condenser. chlorobenzene was distilled off atatmospheric pressure until 800 cc. of distillate had been collected. Theslurry of the sodium salt was stirred while it was allowed to cool toroom temperature.

Meanwhile, free B-diethylaminoethyl chloride was liberated from thehydrochloride as follows: 225 grams of crude B-diethylaminoethylchloride hydrochloride were suspended in 400 cc. of icecoldchlorobenzene. 200 cc. of 50% sodium hydroxide solution were added inportion with stirring, the entire mixture being kept cold in an icebath. The top layer was decanted through a sintered glass funnel. Thebottom aqueous layer was extracted three times with 200 cc. portions ofchlorobenzene. All the chlorobenzene extracts were combined and driedover magnesium sulfate in a refrigerator.

The chlorobenzene solution of the B-diethylaminoethyl chloride wasfiltered from the magnesium sulfate, the filtrate was added to theslurry of the sodium salt of p-hydroxyphenyl styryl ketone, andthemixture was stirred and refluxed for 4 hours. The chlorobenzene wasremoved by steam distillation and the residue was allowed to cool toroom temperature. The oily base was extracted into two 400 cc. portionsof ether, the combined ether extracts were dried over magnesium sulfate,and the solvent was removed in vacuo. The base, p-(p-diethylaminoethoxy)phenyl styryl ketone, was dissolved in 400 cc. of ethanol, a solution of83 grams of oxalic acid dihydrate in 250 cc. of warm ethanol was added,and the resulting solution was allowed to cool to 30 C. Ether (600 cc.)was added, the slightly turbidsolution was seeded, and the mixturewasallowed to stand in a cool place to crystallize. The product wasp-(e-diethylaminoethoxy)phenyl styryl ketone oxalate of M. P. 152-153?C. A sample, recrystallized three times from 97% ethanol, melted at151-152 C.

p-(e-Diethylaminoethozcy) phenyl styryl ketone hydrobromide 4 grams ofthe oxalate, prepared as above, were partitioned between 120 cc. ofether, 150 cc. of

water and 10 cc. of 50% sodium hydroxide solusium sulfate and, afterremoval of the solvent, the

residue was dissolved in 3 cc. of ethanol and this solutionwas treatedwith 3 cc. of alcoholic hydrogen bromide. On cooling, the solution setto a mass of white crystals. The product, recrystallized from 15.00. ofethanol, melted at 170-l'72 C.

9 (43 Diethylaminoethowy)phenyl phenethyl ketone oxalate Palladium oxide(8. grams), suspended in 100 cc. ofethanol, was pre-reduced in a Parrhydroeenation apparatus. Mostv of the alcohol was decanted from thecatalyst and a solution of 41.3 grams of p (/3 diethylaminoethoxy)phenyl styryl ketone oxalate in 150 cc. of ethanol and 75 cc. of waterwas added to the catalyst. The mixture was. shaken with hydrogen at aninitial pressureof 385p. s. i. Absorption of the gas ceased when 0.1mole hadbeen taken up. The catalyst was then filtered off and thesolvent removed in vacuo. The residual oil was stored in a vacuumdesiccator over phosphorus pentoxide for 2 days. The oil was thendissolved in 300 cc. of warm acetonitrile, the solution was filtered,and the mother liquor, on. cooling and seeding, deposited a massof-white crystals. M. P. fi l-66 C. Recrystallized from 225cc. ofacetonitrile, the product, p-(fl-diethylaminoethoxy) phenyl-phenethylketone'roxalate, was pure white. M. P. 64-66 C.

p piethylaminoethoxymhenyl phenethyl ketone hydrobromz'de In; a. mannersimilar to the, production of the oxalate, the hydrobromide may beprepared by hydrogenation of the corresponding styryl ketone U'tion. Theether layer was dried over inagne- I hydrobromide, whose production isshown above.

p (e Diethylaminoethomymhenyl phenethyl ketone A solution of 11.5 gramsof p-(B-diethylaminoethoxy phenyl-phenethy1 ketone oxalate in 250 cc. ofwater wastreated with 30 cc. of 4 N sodium hydroxide solution. Theprecipitated base was extracted with two 200 cc. portions of ether.After drying the combined ether extracts with magnesium sulfate, thesolvent was removed in vacuo. The residual oilyp-(e-diethylaminoethoxy)phenyl-phenethyl ketone weighed 8.3 rams.

in (B Diethylaminoethowwphenyz phenethyl ketone citrate CIHIS and theacid addition salts thereof.

2. p- (e-Diethylaminoethoxy) phenyl-phenethyl ketone.

3. p,- (e-Diethylaminoethoxy) phenyl-phenethyl ketone oxalate.

4.. p-- (p-Diethylaminoethoxy), phenyl-phenethyl ketone citrate.

5. p- (p-Diethylaminoethoxy) phenyl-phenethyl ketone hydrobromide.

6. p- (e-Diethylaminoethoxy) phenyl-phenethyl ketone hydrochloride.

MOSES WOLF GOLDBERG.. ALBERT ISRAEL RACHLIN.

References Cited in the file of this patent UNITED STATES PATENTS NameDate- Hartmann et a1. Jan. 17, 1933 Number

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF P-(B -DIETHYLAMINOETHOXY) PHENYLPHENETHYL KETONE HAVING THE FORMULA